Details

Autor(en) / Beteiligte

• Zheng, Qiuyang
• Song, Beibei
• Li, Guilin
• Cai, Fang
• Wu, Meiling
• Zhao, Yingjun
• Jiang, LuLin
• Guo, Tiantian
• Shen, Mingyu
• Hou, Huan
• Zhou, Ying
• Zhao, Yini
• Di, Anjie
• Zhang, Lishan
• Zeng, Fanwei
• Zhang, Xiu-Fang
• Luo, Hong
• Zhang, Xian
• Zhang, Hongfeng
• Zeng, Zhiping
• Huang, Timothy Y
• Dong, Chen
• Qing, Hong
• Zhang, Yun
• Zhang, Qing
• Wang, Xu
• Wu, Yili
• Xu, Huaxi
• Song, Weihong
• Wang, Xin

Titel

USP25 inhibition ameliorates Alzheimer's pathology through the regulation of APP processing and Aβ generation

Ist Teil von

• The Journal of clinical investigation, 2022-03, Vol.132 (5), p.1-12

Ort / Verlag

United States: American Society for Clinical Investigation

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• Down syndrome (DS), or trisomy 21, is one of the critical risk factors for early-onset Alzheimer's disease (AD), implicating key roles for chromosome 21-encoded genes in the pathogenesis of AD. We previously identified a role for the deubiquitinase USP25, encoded on chromosome 21, in regulating microglial homeostasis in the AD brain; however, whether USP25 affects amyloid pathology remains unknown. Here, by crossing 5×FAD AD and Dp16 DS mice, we observed that trisomy 21 exacerbated amyloid pathology in the 5×FAD brain. Moreover, bacterial artificial chromosome (BAC) transgene-mediated USP25 overexpression increased amyloid deposition in the 5×FAD mouse brain, whereas genetic deletion of Usp25 reduced amyloid deposition. Furthermore, our results demonstrate that USP25 promoted β cleavage of APP and Aβ generation by reducing the ubiquitination and lysosomal degradation of both APP and BACE1. Importantly, pharmacological inhibition of USP25 ameliorated amyloid pathology in the 5×FAD mouse brain. In summary, we identified the DS-related gene USP25 as a critical regulator of AD pathology, and our data suggest that USP25 serves as a potential pharmacological target for AD drug development.